Method for treating diabetes mellitus in a patient

ABSTRACT

The need for the delivery of insulin by injection can be reduced or eliminated by delivering aerosolized insulin. Repeatability of dosing is obtainable by using either regular insulin or monomeric insulin. When delivering insulin (not monomeric) by inhalation, the total inhaled volume should be about the same at each delivery to obtain repeatable results. The patient can be coached (by teaching) to inhale a given amount of air and can also be coached (by teaching) to inhale at a given flow rate. Further, the rate at which blood glucose is lowered is increased by the use of monomeric insulin. Particles of insulin and monomeric insulin delivered to the surface of lung tissue will be absorbed into the circulatory system. A dry powder or a liquid insulin formulation is delivered to the patient from a mechanical or electronic hand-held, self-contained device.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 09/848,772,filed May 3, 2001 now abandoned, which is a continuation of applicationSer. No. 09/656,535, filed Sep. 7, 2000 now U.S. Pat. No. 6,250,298,which is a continuation of application Ser. No. 09/004,756, filed Jan.8, 1998 (now U.S. Pat. No. 6,131,567 issued on Oct. 17, 2000), which isa continuation-in-part of application Ser. No. 08/792,616, filed Jan.31, 1997 (now U.S. Pat. No. 5,888,477 issued on Mar. 30, 1999), which isa continuation-in part of application Ser. No. 08/754,423 filed Nov. 22,1996 (now U.S. Pat. No. 5,743,250 issued on Apr. 28, 1998), which is acontinuation-in-part of application Ser. No. 08/549,343, filed on Oct.27, 1995 and issued as U.S. Pat. No. 5,915,378 on Jun. 29, 1999 which isa continuation-in-part of application Ser. No. 08/331,056 filed Oct. 28,1994 and issued as U.S. Pat. No. 5,672,581 on Sep. 30, 1997, which is acontinuation-in-part of application Ser. No. 08/011,281 filed on Jan.29, 1993 and issued as U.S. Pat. No. 5,364,838 on Nov. 15, 1994, all ofwhich are hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates generally to a method of aerosolized drugdelivery. More specifically, this invention relates to the controlledintrapulmonary delivery of a monomeric insulin alone or in combinationwith other treatment methodologies which are combined to significantlyreduce or eliminate the need for administering insulin by injection.

BACKGROUND OF THE INVENTION

Diabetes Mellitus is a disease affecting approximately 7.5 millionpeople in the United States. The underlying cause of this disease isdiminished or absent insulin production by the Islets of Langerhans inthe pancreas. Of the 7.5 million diagnosed diabetics in the UnitedStates, approximately one-third are treated using insulin replacementtherapy. Those patients receiving insulin typically self-administer oneor more doses of the drug per day by subcutaneous injection. Insulin isa polypeptide with a nominal molecular weight of 6,000 Daltons. Insulinhas traditionally been produced by processing pig and cow pancreas toallow isolation of the natural product. More recently, recombinanttechnology has made it possible to produce human insulin in vitro. It isthe currently common practice in the United States to institute the useof recombinant human insulin in all of those patients beginning insulintherapy.

It is known that most proteins are rapidly degraded in the acidicenvironment of the GI tract. Since insulin is a protein which is readilydegraded in the GI tract, those in need of the administration of insulinadminister the drug by subcutaneous injection (SC). No satisfactorymethod of orally administering insulin has been developed. The lack ofsuch an oral delivery formulation for insulin creates a problem in thatthe administration of drugs by injection can be both psychologically andphysically painful.

In an effort to provide for a non-invasive means for administeringinsulin, and thereby eliminate the need for hypodermic syringes,aerosolized insulin formulations have been tested. Aerosolized insulinformulations have been shown to produce insulin blood levels in man whenthese aerosols are introduced onto nasal or pulmonary membrane. Moses etal. [Diabetes, Vol. 32, November 1983] demonstrated that a hypoglycemicresponse could be produced following nasal administration of 0.5units/kg. Significant inter-subject variability was noted, and the nasalinsulin formulation included unconjugated bile salts to promote nasalmembrane penetration of the drug. Salzman et al. [New England Journal ofMedicine, Vol. 312, No. 17] demonstrated that an intranasal aerosolizedinsulin formulation containing a non-ionic detergent membranepenetration enhancer was effective in producing a hypoglycemic responsein diabetic volunteers. Their work demonstrated that nasal irritationwas present in varying degrees among the patients studied. In thatdiabetes is a chronic disease which must be continuously treated by theadministration of insulin and in that mucosal irritation tends toincrease with repeated exposures to the membrane penetration enhancers,efforts at developing a non-invasive means of administering insulin vianasal administration have not been commercialized.

In 1971, Wigley et al. [Diabetes, Vol 20, No. 8] demonstrated that ahypoglycemic response could be observed in patients inhaling an aqueousformulation of insulin into the lung. Radio-immuno assay techniquesdemonstrated that approximately 10 percent of the inhaled insulin wasrecovered in the blood of the subjects. Because the surface area ofmembranes available to absorb insulin is much greater in the lung thanin the nose, no membrane penetration enhancers are required for deliveryof insulin to the lungs by inhalation. The inefficiency of delivery seenby Wigley was greatly improved in 1979 by Yoshida et al. [Journal ofPharmaceutical Sciences, Vol. 68, No. 5] who showed that almost 40percent of insulin delivered directly into the trachea of rabbits wasabsorbed into the bloodstream via the respiratory tract. Both Wigley andYoshida showed that insulin delivered by inhalation could be seen in thebloodstream for two or more hours following inhalation.

Aerosolized insulin therefore can be effectively given if the aerosol isappropriately delivered into the lung. In a review article, DieterKohler [Lung, supplement pp. 677-684] remarked in 1990 that multiplestudies have shown that aerosolized insulin can be delivered into andabsorbed from the lung with an expected absorption half-life of 15-25minutes. However, he comments that “the poor reproducibility of theinhaled dose [of insulin] was always the reason for terminating theseexperiments.” This is an important point in that the lack of precisereproducibility with respect to the administration of insulin iscritical. The problems associated with the inefficient administration ofinsulin cannot be compensated for by administering excess amounts of thedrug in that the accidental administration of too much insulin could befatal.

Effective use of an appropriate nebulizer can achieve high efficiency indelivering insulin to human subjects. Laube et al. [Journal of AerosolMedicine, Vol. 4, No. 3, 1991] have shown that aerosolized insulindelivered from a jet nebulizer with a mass median aerodynamic diameterof 1.12 microns, inhaled via a holding chamber at a slow inspiratoryflow rate of 17 liters/minute, produced an effective hypoglycemicresponse in test subjects at a dose of 0.2 units/kg. Colthorpe et al.[Pharmaceutical Research, Vol. 9, No. 6, 1992] have shown thataerosolized insulin given peripherally into the lung of rabbits producesa blood concentration versus time profile of over 50 percent in contrastto 5.6 percent blood concentration versus time profile seen for liquidinsulin dripped onto the central airways. Colthorpe's work supports thecontention that aerosolized insulin must be delivered peripherally intothe lung for maximum efficiency and that inadvertent central depositionof inhaled aerosolized insulin will produce an effect ten times lowerthan that desired. Variations in dosing of 10-fold are clearlyunacceptable with respect to the administration of most drugs, and inparticular, with respect to the administration of insulin.

The present invention endeavors to provide a non-invasive methodologyfor enhancing treatment of diabetic patients via aerosolized delivery.

SUMMARY OF THE INVENTION

Aerosolized delivery of insulin is disclosed wherein the insulin ismonomeric insulin. Aerosolized delivery of monomeric insulin issignificantly less affected by an inhaling patient's breathing patternas compared to the effect on conventional recombinant insulin. Morespecifically, the maximum insulin concentration (C_(MAX)) and the timeneeded to obtain the maximum concentration (T_(MAX)) are much lessaffected by the amount of air inhaled after delivery of aerosolizeddrug. Accordingly, a higher degree of repeatability of dosing can beobtained (with monomeric insulin as compared to regular insulin) makingit substantially more practical for patients to control glucose levelsby inhaling insulin—thereby making diabetics less dependent on injectinginsulin.

When delivering aerosolized insulin the patient can be coached (byteaching and/or by the device which measures flow rate and/or volume) toinhale at a given rate and to inhale a given amount of air (before andafter the aerosol is released). One of the findings disclosed here isthat the inhaled volume at delivery does not substantially affect theblood concentration versus time profile for the aerosolized delivery ofmonomeric insulin. However, the inhaled volume at delivery doessubstantially affect the blood concentration versus time profile ofregular insulin. Accordingly, one aspect of the invention is theaerosolized delivery of monomeric insulin without regard to respiratorymaneuver parameters such as inhaled volume. A second aspect of theinvention is aerosolized delivery of insulin which is not monomericinsulin while measuring inhaled volume and insuring that the inhaledvolume is (1) repeated for each dose in the same amount and (2)preferably a large inhaled volume, e.g. 80% or more of the lung capacityof the patient. It should be noted that to obtain the most repeatableresults that monomeric insulin should be delivered each time atsubstantially the same inspiratory flow rate and inspiratory volume atdelivery and such delivery should be followed by the same inhaled volumewhich is preferably a maximum inhaled volume.

The monomeric insulin formulation may be in any form, e.g., a drypowder, or dispersed or dissolved in a low boiling point propellant.However, the formulation is more preferably an aqueous solution having apH close to 7.4±1.0 which can be aerosolized into particles having aparticle diameter in the range of about 1.0 to about 4.0 microns.Formulations of monomeric insulin are preferably aerosolized andadministered via hand-held, self-contained devices which areautomatically actuated at the same release point in a patient'sinspiratory flow cycle. The release point is automatically determinedeither mechanically or, more preferably calculated by a microprocessorwhich receives data from a sensor making it possible to determineinspiratory flow rate and inspiratory volume. The device can measureparameters including inspiratory flow rates and volumes and provideinformation to the patient which can aid in controlling the patient'srespiratory maneuvers. Preferably the device is loaded with a cassettecomprised of an outer housing which holds a package of individualdisposable collapsible containers of a monomeric insulin analogcontaining formulation for systemic delivery. Actuation of the deviceforces the monomeric insulin formulation through a porous membrane ofthe container which membrane has pores having a diameter in the range ofabout 0.25 to 3.0 microns, preferably 0.25 to 1.5 microns. The porousmembrane is positioned in alignment with a surface of a channel throughwhich a patient inhales air.

The dose of insulin analog to be delivered to the patient varies with anumber of factors—most importantly the patient's blood glucose level.Thus, the device can deliver all or any proportional amount of theformulation present in the container. If only part of the contents areaerosolized the remainder may be discarded. By delivering anyproportional amount of a container the patient can adjust the dose toany desired level while using containers which all contain the sameamount of monomeric insulin.

Smaller particle sizes are preferred to obtain systemic delivery ofinsulin analog. Thus, in one embodiment, after the aerosolized mist isreleased into the channel the air surrounding the particles may beheated in an amount sufficient to evaporate carrier and thereby reduceparticle size. The air drawn into the device can be actively heated bymoving the air through a heating element which element is pre-heatedprior to the beginning of a patient's inhalation. The amount of energyadded can be adjusted depending on factors such as the desired particlesize, the amount of the carrier to be evaporated, the water vaporcontent of the surrounding air and the composition of the carrier (seeU.S. Pat. No. 5,522,385 issued Jun. 4, 1996).

To obtain systemic delivery it is desirable to get the aerosolizedformulation deeply into the lung. This is obtained, in part, byadjusting particle sizes. Particle diameter size is generally about oneto three times the diameter of the pore from which the particle isextruded. In that it is technically difficult to make pores of 1.0micron or less in diameter the use of evaporation can reduce particlesize to 3.0 microns or less even with pore sizes well above 1 micron.Energy may be added in an amount sufficient to evaporate all orsubstantially all carrier and thereby provide particles of dry powderedinsulin or highly concentrated insulin formulation to a patient whichparticles are uniform in size regardless of the surrounding humidity andsmaller due to the evaporation of the carrier.

In addition to adjusting particle size, systemic delivery of insulin isobtained by releasing an aerosolized dose at a desired point in apatient's respiratory cycle. When providing systemic delivery it isimportant that the delivery be reproducible.

Reproducible dosing of insulin to the patient is obtained by: (1) usingmonomeric insulin which has been shown here to be less affected by thepatient's respiratory pattern, and/or; (2)providing for automaticrelease of formulation in response to a determined inspiratory flow rateand measured inspiratory volume. The automatic release method involvesmeasuring for, determining and/or calculating a firing point or drugrelease decision based on instantaneously (or real time) calculated,measured and/or determined inspiratory flow rate and inspiratory volumepoints. To obtain repeatability in dosing, the formulation is repeatedlyreleased at the same measured (1) inspiratory flow rate and (2)inspiratory volume. To maximize the efficiency of delivery aerosols arereleased at (3) a measured inspiratory flow rate in the range of fromabout 0.1 to about 2.0 liters/second and (2) a measured inspiratoryvolume in the range of about 0.1 to about 1.5 liters. After the aerosolis released the patient preferably continues inhaling to a maximuminhalation point.

A primary object of the invention is to provide for a method ofincreasing the repeatability at which glucose levels can be controlledby aerosol delivery of monomeric insulin.

An advantage of the invention is that the aerosolized delivery ofmonomeric insulin is substantially less affected by a patient'sbreathing maneuvers during delivery as compared to regular insulin andspecifically is less affected by how much the patient inhales afteraerosolized delivery.

A feature of the invention is the commercially available insulin lisprocan be used in the method.

Another object is to provide a method of administering a monomericinsulin analog formulation to a patient wherein the formulation isrepeatedly delivered to a patient at the same measured inspiratory flowrate (in the range of 0.1 to 2.0 liters/second) and separatelydetermined inspiratory volume (beginning delivery in the range of 0.15to 1.5 liters and continuing inspiration to maximum, e.g., 4-5 liters).

Another object of the invention is to combine delivery therapies forinhaling monomeric insulin with monitoring technologies so as tomaintain tight control over the serum glucose level of a patientsuffering from diabetes mellitus.

Another object of the invention is to provide a device which allows forthe intrapulmonary delivery of controlled amounts of monomeric insulinformulation based on the particular needs of the diabetic patientincluding serum glucose levels and insulin sensitivity.

Another object of the invention is to provide a means for treatingdiabetes mellitus which involves supplementing monomeric insulinadministration using an intrapulmonary delivery means in combinationwith injections of insulin and/or oral hypoglycemic agents such assulfonylureas.

Another advantage of the present invention is that the methodologyallows the administration of a range of different size doses ofmonomeric insulin by a convenient and painless route, thus decreasingthe probability of insulin overdosing and increasing the probability ofsafely maintaining desired serum glucose levels.

Another feature of the device of the present invention is that it may beprogrammed to provide variable dosing (from the same size container) sothat different doses are delivered to the patient at different times ofthe day coordinated with meals and/or other factors important tomaintain proper serum glucose levels with the particular patient.

Another feature of the invention is that the portable, hand-heldinhalation device of the invention can be used in combination with aportable device for measuring serum glucose levels in order to closelymonitor and titrate dosing based on actual glucose levels.

Yet another feature of the invention is that the microprocessor of thedelivery device can be programmed to prevent overdosing by preventingformulation release more than a given number of times within a givenperiod of time.

Another object of the invention is to adjust particle size by heatingair surrounding the particles in an amount sufficient to evaporatecarrier and reduce total particle size.

Another object is to provide a drug delivery device which includes adesiccator for drying air in a manner so as to remove water vapor andthereby provide consistent particle sizes even when the surroundinghumidity varies.

Another object is to provide a device for the delivery of aerosols whichmeasures humidity via a solid state hygrometer.

A feature of the invention is that drug can be dispersed or dissolved ina liquid carrier such as water and dispersed to a patient as dry orsubstantially dry particles of monomeric insulin.

Another advantage is that the size of the particles delivered will berelatively independent of the surrounding humidity.

It is an object of this invention to demonstrate a novel application forHumalog™ as a monomeric insulin analog well suited for pulmonary drugdelivery.

It is an object of this invention to demonstrate that Humalog™ providesunique benefits when delivered via the lung by reducing the degree towhich lung sequestration occurs following aerosolized delivery.

It is an object of this invention to demonstrate that aerosolizeddelivery of Humalog™ in place of conventional formulations ofrecombinant human insulin makes a repeatable blood concentration versustime profile substantially less dependent on the patients final inhaledvolume at delivery.

It is an object of this invention to demonstrate that by increasing theblood concentration versus time profile of the delivered monomericinsulin such as Humalog™ (regardless of breathing maneuver afterdelivery) that a more reproducible and consistent effect on serum bloodglucose can be achieved.

It is another object of this invention to demonstrate that the increasedreproducibility seen after the delivery of Humalog™ via aerosolizationinto the lung results in a more economical approach to the pulmonarydrug delivery of insulin than offered by the delivery of regularrecombinant human insulin to the lung via aerosolization.

These and other objects, advantages and features of the presentinvention will become apparent to those persons skilled in the art uponreading the details of the structure of the device, formulation ofcompositions and methods of use, as more fully set forth below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph plotting the change in serum insulin levels over timefollowing different methods of insulin administration;

FIG. 2 is a graph plotting the change in immunoreactive insulin in bloodserum over time following different methods of insulin lisproadministration.

FIG. 3 is a graph showing V_(L) and V_(H) in a preferred breathingpattern at delivery.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Before the present method of delivering aerosolized monomeric insulin totreat diabetes mellitus and devices, containers and formulations used inthe treatment are described, it is to be understood that this inventionis not limited to the particular methodology, containers, devices andformulations described, as such methods, devices and formulations may,of course, vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to limit the scope of the present invention which willbe limited only by the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “and,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “aformulation” includes mixtures of different formulations, reference to“an analog” refers to one or mixtures of insulin analogs, and referenceto “the method of treatment” includes reference to equivalent steps andmethods known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods, devicesand materials similar or equivalent to those described herein can beused in the practice or testing of the invention, the preferred methods,devices and materials are now described. All publications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing devices, formulations and methodologies whichare described in the publication and which might be used in connectionwith the presently described invention.

Publications cited herein are cited for their disclosure prior to thefiling date of the present application. Nothing here is to be construedas an admission that the inventors are not entitled to antedate thepublications by virtue of an earlier priority date or prior date ofinvention. Further the actual publication dates may be different fromthose shown and require independent verification.

DEFINITIONS

The term “insulin” shall be interpreted to encompass fast acting“regular” insulin, natural extracted human insulin, recombinantlyproduced human insulin, insulin extracted from bovine and/or porcinesources, recombinantly produced porcine and bovine insulin and mixturesof any of these insulin products. The term is intended to encompass thepolypeptide normally used in the treatment of diabetics in asubstantially purified form but encompasses the use of the term in itscommercially available pharmaceutical form which includes additionalexcipients. Regular insulin is preferably recombinantly produced and maybe dehydrated (completely dried) or in solution. For purposes of thepresent invention insulin is particularly characterized by moleculeswhich form complexes, particularly hexamers in solution and when in thehuman body the hexamer complexes disassociate much more slowly thanmonomeric insulin.

The “monomeric insulin” is intended to encompass any form of an insulinmolecule which is different from regular insulin wherein the differenceresults in the insulin molecules not maintaining hexamer complexes in ahuman which hexamers are characteristic of insulin. Monomeric insulinexists predominantly in a monomer form or quickly dissociates into amonomeric form in the human body. The change which induces the monomericform may be caused by one or more of the amino acids within thepolypeptide chain being replaced with an alternative amino acid and/orwherein one or more of the amino acids has been deleted or wherein oneor more additional amino acids has been added to the polypeptide chainor amino acid sequences which act as insulin in decreasing blood glucoselevels and/or where bonds such as disulfide bonds are deleted, added ormoved in position relative to natural human insulin. The change may alsoby obtained by using a different salt form e.g. replacing the zinccations with sodium cations. The preferred monomeric insulin is insulinlispro in a zinc salt form as disclosed in U.S. Pat. No. 5,547,929,issued Aug. 20, 1996 and see also U.S. Pat. Nos. 5,514,646 and 5,700,662all of which are incorporated herein by reference. It should be notedthat insulin as well as monomeric insulin will disassociate intomonomeric forms over time. However, monomeric insulin will disassociateinto the monomeric form, in a human body, at twice the rate or fasterthan insulin when it is administered subcutaneously. It should be notedthat insulin lispro disassociates into the monomeric form atapproximately three times the rate as compared to regular insulin whenit is administered subcutaneously.

The terms “V_(H)” and “high volume” are used interchangeably here andshall mean that after an aerosolized dose is created the patient inhalesthe dose and continues to inhale a high volume. More specifically, thepatient inhales a high volume which is approximately 80% or more of thepatient's total lung capacity. For an adult with a 5 liter lung volumethe inhalation would be approximately 4 liters or more i.e. up to thetotal lung volume. Some error should be accounted for. Thus the highvolume can be 65% to 100% of the total lung volume depending on the lungvolume of the patient. Within the specific examples shown here the highinhaled volume for healthy male patients with a total lung volume ofapproximately 5 liters was in general about 4.7 liters. High volume ispreferably as close to 100% as the patient can inhale.

The terms “V_(L)” and “Low volume” refer to a smaller inhaled volume ascompared to an inhaled high volume of air with the aerosolized deliveryof insulin. Even without inhaling the lung will retain some air. Thus, alow inhaled volume is approximately 40% plus or minus 15% of thepatient's total lung volume. For the experiments shown here a lowinhaled volume involved inhaling approximately 3 liters or less. Itshould be noted that inhaled volumes are volumes recorded at BodyTemperature and Pressure Standard, i.e. the units are liters (btps). Theterms V_(L) V_(H) can be further understood in connection with FIG. 3and it description.

The term “acceptable serum glucose level” is intended to mean a glucoselevel above 50 mg/dl and below 300 mg/dl, more preferably 80 mg/dl to200 mg/dl and most preferably about 100 mg/dl. It will be understood bythose skilled in the art that levels of about 50 mg/dl are consideredlow and that levels of about 300 mg/dl are considered high, althoughacceptable in the sense that these levels are generally not fatal. It isan important aspect of the invention to maintain more acceptable levelswhich are above the low of 50 mg/dl and below the high of 300 mg/dl withit being more acceptable to deliver doses of insulin so as to keep thepatient as close as possible to about 100 mg/dl.

The term “blood concentration versus time profile” shall be interpretedto mean the concentration of a drug in the blood or plasma over time.This can be characterized by means of a graph showing the concentrationof a drug (e.g. insulin or an insulin analog or “immunoreactive insulin”as a surrogate measurement for an insulin analog such as insulin lispro)on the Y axis and time on the X axis. The blood concentration versustime profile can also be characterized by certain pharmacokineticparameters such as C_(max) (the maximum concentration of the drug seenover the measured time interval) and T_(max) (the time at which C_(max)was observed). Note that, by these criteria, two different bloodconcentration versus time profiles may be associated with similar oreven identical bioavailability measurements. The blood concentrationversus time profile is crucial for drugs such as insulin and insulinanalogs where the time at which peak concentration preferably occurs inconjunction with peak blood glucose levels following a meal. Differentvalues of T_(max) for two different insulin preparations or deliverymethods could therefore be associated with significant differences insafety and efficacy.

The term “dosing event” shall be interpreted to mean the administrationof regular insulin and/or monomeric insulin to a patient in need thereofby the intrapulmonary route of administration which event may encompassone or more releases of formulation from a dispensing device (from oneor more containers) over a period of time of 15 minutes or less,preferably 10 minutes or less, and more preferably 5 minutes or less,during which period one or more inhalations are made by the patient andone or more doses of regular insulin or monomeric insulin are releasedand inhaled. A dosing event shall involve the administration of regularinsulin or monomeric insulin to the patient in an amount of about 1 unitto about 30 units in a single dosing event which may involve the releaseof from about 1 to about 300 units from the device.

The term “inspiratory flow rate” shall mean a value of air flow ratemeasured, calculated and/or determined based on the speed of the airpassing a given point in a measuring device assuming atmosphericpressure ±5% and a temperature in the range of about 10° C. to 40° C.

The term “inspiratory flow” shall be interpreted to mean a value of airflow calculated based on the speed of the air passing a given pointalong with the volume of the air that has passed that point with thevolume calculation being based on integration of the flow rate data andassuming atmospheric pressure, ±5% and temperature in the range of about10° C. to about 40° C.

The term “inspiratory volume” shall mean a determined, calculated and/ormeasured volume of air passing a given point into the lungs of a patientassuming atmospheric pressure ±5% and a temperature in the range of 10°C. to 40° C.

The term “inhaling maximally” shall mean that the patient makes amaximal effort to inhale air into the lungs.

The term “inspiratory flow profile” shall be interpreted to mean datacalculated in one or more events measuring inspiratory flow andcumulative volume, which profile can be used to determine a point withina patient's inspiratory cycle which is preferred for the release ofaerosol to be delivered to a patient. The point within the inspiratorycycle where drug is released may be based on a point within theinspiratory cycle likely to result in the maximum delivery of drugand/or based on a point in the cycle most likely to result in thedelivery of a reproducible amount of drug to the patient at each releaseof drug. Repeatability of the amount delivered is the primary criterionand maximizing the amount delivered is an important but secondarycriterion. Thus, a large number of different drug release points mightbe selected and provide for repeatability in dosing provided theselected point is again selected for subsequent releases. To insuremaximum drug delivery the point is selected within given parameters.

The term “therapeutic index” refers to the therapeutic index of a drugdefined as the ratio of toxic to therapeutic dose. Drugs with atherapeutic index near unity achieve their therapeutic effect at dosesvery close to the toxic level and as such have a narrow therapeuticwindow, i.e. a narrow dose range over which they may be administered.

The term “liquid formulation” is used herein to describe anypharmaceutically active insulin, including insulin and/or monomericinsulin for treating diabetes mellitus by itself or with apharmaceutically acceptable carrier in flowable liquid form andpreferably having a viscosity and other characteristics such that theformulation is aerosolized into particles which are inhaled into thelungs of a patient after the formulation is moved through a porousmembrane of the invention. Such formulations are preferably solutions,e.g. aqueous solutions, ethanolic solutions, aqueous/ethanolicsolutions, saline solutions and colloidal suspensions. Formulations canbe solutions or suspensions of drug in any fluid including fluids in theform of a low boiling point propellant.

The term “formulation” is used to encompass the term “liquidformulation” and to further include dry powders of insulin and/ormonomeric insulin along with excipient materials. Preferred formulationsare aqueous solutions of monomeric insulin but include dry powders anddispersions.

The term “substantially” dry shall mean particles of an aerosol whichcontain less than 10% free water, ethanol or other liquid carrier basedon total weight and preferably contains no detectable free liquidcarrier.

The term “bulk flow rate” shall mean the average velocity at which airmoves through a channel considering that the flow rate is at a maximumin the center of the channel and at a minimum at the inner surface ofthe channel.

The term “flow boundary layer” shall mean a set of points defining alayer above the inner surface of a channel through which air flowswherein the air flow rate below the boundary layer is substantiallybelow the bulk flow rate, e.g., 50% or less than the bulk flow rate.

The term “carrier” shall mean a non-active portion of a formulation. Inaqueous formulations, it is a liquid, flowable, pharmaceuticallyacceptable excipient material which insulin and/or monomeric insulin issuspended in or more preferably dissolved in. In a dry powder, it shallinclude non-active components, e.g., to keep the particles separate.Useful carriers do not adversely interact with the monomeric insulin andhave properties which allow for the formation of aerosolizedparticles—preferably particles having a diameter in the range of 0.5 to3.0 microns when a formulation comprising the carrier and insulin analogis forced through pores having a diameter of 0.25 to 3.0 microns.Preferred carriers for liquid solutions include water, ethanol andmixtures thereof. Other carriers can be used provided that they can beformulated to create a suitable aerosol and do not adversely affectinsulin, monomeric insulin or human lung tissue.

The term “measuring” describes an event whereby either the inspiratoryflow rate or inspiratory volume of the patient is measured (viaelectronic sensors or by mechanical means) in order to determine anoptimal point in the inspiratory cycle at which to release aerosolizeddrug. An actual measurement of both rate and volume may be made or therate can be directly measured and the volume calculated based on themeasured rate. It is also preferable to continue measuring inspiratoryflow during and after any drug delivery and to record inspiratory flowrate and volume before, during and after the release of drug. Suchreading makes it possible to determine if drug was properly delivered tothe patient.

Each of the parameters discussed above is measured during quantitativespirometry. A patient's individual performance can be compared againsthis personal best data, individual indices can be compared with eachother for an individual patient (e.g. FEV₁ divided by FVC, producing adimensionless index useful in assessing the severity of acute asthmasymptoms), or each of these indices can be compared against an expectedvalue. Expected values for indices derived from quantitative spirometryare calculated as a function of the patient's sex, height, weight andage.

General Methodology

The invention comprises aerosolizing a formulation of monomeric insulin(e.g. insulin lispro) and inhaling the aerosolized formulation into thelungs. Although the inhalation of insulin which results in the insulinentering the circulatory system is known, correctly dosing the amount ofinsulin delivered by inhalation has been problematic—however, see U.S.Pat. No. 5, 672,581 issued Sep. 30, 1997. The devices, formulations andmethods disclosed herein are useful in solving problems with priormethods. For example, when regular insulin is delivered to a patient byinhalation the amount of effect on glucose levels varies considerablybased on the lung volume inhaled by the patient with the aerosolizedinsulin at delivery. If the blood glucose level is not quickly loweredthe patient may administer additional insulin which in combination withthat already administered will dangerously lower the blood glucoselevel. The present invention endeavors to provide a preferred bloodconcentration versus time profile by the delivery of monomeric insulinwhich rapidly disassociates into its monomeric form in a human and assuch moves into the circulatory system more rapidly as compared toregular insulin. When regular insulin is delivered by inhalation, theeffect on lowering glucose levels is often different depending on thetotal inhaled volume of by the patient at delivery. Results providedhere show that the delivery of monomeric insulin is much less effectedby the patient's total inhaled volume at delivering as compared to theaerosolized delivery of regular insulin thereby improving repeatabilityof dosing. Thus, the data shown here provide improved unexpected resultswith respect to a practical method of treating Diabetes Mellitus byaerosolized drug delivery.

FIGS. 1 and 2 along with tables 1 and 2 dramatically show how the totalinhaled volume at delivery has a dramatically greater effect on theblood concentration versus time profile following aerosolized deliveryof insulin as compared to aerosolized delivery of monomeric insulin. Intables 1 and 2 as well as within FIGS. 1 and 2 a reference is made to“V_(L)” and “V_(H)” which refers to low volume and high volumeinhalations at delivery respectively. A more complete understanding ofwhat is meant by these terms and how the invention is carried out can beunderstood by reference to FIG. 3.

FIG. 3 is a graph of inspiratory volume verses inspiratory flow rate inliters per second. Regardless of whether one is delivering insulin ormonomeric insulin it is preferable to begin the release of theaerosolized dose to the patient when the inhaled inspiratory volume andinspiratory flow rate are within the parameters of the rectangle 1 shownin FIG. 3. In the specific example of FIG. 3 the release occurs at thepoint 2. The parameters of the rectangle shown indicate that releaseshould occur at an inspiratory volume above 0.1 liter and prior to 0.8liter. Further, the aerosol is released after the patients inhalationrate exceeds 0.1 liters per second but prior to the rate exceeding the2.0 liters per second. In the examples shown the release occurs at aninspiratory volume of about 0.5 liters and at an inspiratory rate ofabout 1.0 liters per second. To enhance repeatability of dosing thepatient would deliver each dose of insulin thereafter at the sameinspiratory volume and inspiratory flow rate. More specifically thedevice of the invention will automatically release the aerosolized doseafter it records an inspiratory volume of about 0.5 liters and aninspiratory flow rate of about 1 liter per second. Thereafter, thepatient is coached to continue inhalation at the same rate e.g. at arate of about 1 liter per second. For a low volume maneuver theinhalation is continued until the patient has inhaled 2 liters of air asshown by the point 3 in FIG. 3. For a high volume maneuver the patientcontinues inhaling until the patient has inhaled 4 liters of air or moreas shown by point 4 in FIG. 3.

A comparison of FIGS. 1 and 2 as well as tables 1 and 2 shows thatinhaling to a low or high volume at delivery does not effect the resultssignificantly results when delivering monomeric insulin—butsubstantially effects results when delivering insulin.

The preferred monomeric insulin is insulin lispro as described in the1997 PDR at page 1488 (incorporated herein by reference). This preferredmonomeric insulin is also referred to herein by the commercial name“Humalog™.” The following provides a description of the conceptual basisof the present invention.

Insulin has been used for over 50 years for the management of diabetesmellitus. Insulin is a naturally occurring hormone which plays aclinical role in glucose metabolism and its absence in patients withType I Diabetes is a fatal illness unless exogenous insulin is used aspart of an insulin replacement therapy program.

Patients have self administered insulin subcutaneously (SC) for decadesas a means for managing their diabetes. The total daily dose of insulinrequired by individual patients varies. The availability of portableblood glucose monitors over the last decade has been a significantadvancement in that patients can now measure their own blood glucoselevels in self dose insulin by injection according to their needs. Manythings affect the daily requirement for insulin. These multiple factorsrequire that patients measure blood glucose levels to achieve tightcontrol of their blood glucose.

The Diabetes Complications and Control Trial (DCCT), a multicenter studydesigned to evaluate the potential long term beneficial effects of tightblood glucose control, was recently completed. This study demonstratedthat insulin requiring diabetics who maintained their serum glucosewithin a specific range over time had a significantly reducedcomplication rate, including the avoidance of the consequences ofperipheral vascular disease (e.g. renal failure, chronic diabeticretinopathy and lower extremity problems).

A key element in the attainment of a stable blood glucose level overtime involves the administration of subcutaneously administered insulinprior to mealtime. In this way, blood levels of insulin will appearcoincident with the increase in blood glucose associated with mealdigestion. Recombinant human insulin, which has been available for overmore than 10 years, is available in a short acting form (regularinsulin) which is appropriate for self administration by injection priorto meal time. Unfortunately, recombinant human insulin must be dosed byinjection approximately one half hour prior to meal time in order toinsure that a rise in blood glucose does not occur unopposed byexogenous insulin levels.

The requirement that recombinant human insulin be injected one half hourprior to meal time is burdensome because it requires that patientsprecisely anticipate the times they will be eating. Eli Lilly hasrecently introduced insulin lispro which is sold as Humalog™ (arecombinant human insulin analog), which is more rapidly absorbed thanrecombinant human insulin when injected subcutaneously. Because it worksmore quickly than recombinant human insulin, Humalog™ can be given justprior to mealtime thereby reducing the burden on the patient to planahead prior to eating.

Recombinant human insulin in aqueous solution is in a hexamericconfiguration. In other words, six molecules of recombinant insulin arenoncovalently associated in a hexameric complex when dissolved in waterin the presence of zinc ions. Studies have demonstrated that hexamericinsulin is not rapidly absorbed from the subcutaneous space. In orderfor recombinant human insulin to be absorbed into circulation, thehexameric form must first dissociate into dimer and/or a monomeric formsi.e., these forms are required before the material can transit into theblood stream. This requirement for recombinant human insulin todisassociate from hexameric to dimer or monomeric form prior toabsorption is believed to be responsible for the 30 minutes required fora self administered dose of subcutaneous recombinant human insulin toproduce a measurable therapeutic blood level.

Although Humalog™ exists in solution outside the body as a hexamer, itvery rapidly disassociates into a monomeric form following subcutaneousadministration. Clinical studies have demonstrated that Humalog™ isabsorbed quantitatively faster than recombinant human insulin aftersubcutaneous administration.

To control glucose levels insulin is dosed in units. Because insulin isgenerally in the form of regular insulin and is generally administeredsubcutaneously the units of measurements used here are subcutaneousequivalents of regular insulin.

Because insulin must be administered frequently in order to allowpatients to attain a tight degree of control over their serum glucose,the fact that all insulin products currently need to be delivered byinjection is a hindrance to compliance. Results from a DCCT studydemonstrate that insulin should ideally be administered 4-6 times eachday in order for patients to be likely to achieve an adequate level ofblood glucose control to obtain a reduction in complication rateassociated with diabetes. A non-invasive method for the delivery ofinsulin could be beneficial in increasing patient compliance withfrequent self administration of insulin throughout the day.

The noninvasive delivery of proteins and peptides has been an elusivegoal of the drug delivery industry. Because proteins are rapidlydisassociated in the GI tract, oral forms for the delivery of proteinsas tablets or capsules have thus far seen limited success. Inhalationaldrug delivery has been demonstrated to be a viable option for thedelivery of proteins and peptides such as insulin via the lung, see U.S.Pat. No. 5,364,838, issued Nov. 15, 1994 and U.S. Pat. No. 5,672,581issued Sep. 30, 1997.

Recent studies have demonstrated that insulin can be reproduciblyadministered for inhalation to healthy volunteers producing a rapid risein measurable serum glucose level as well as a rapid fall in bloodglucose. U.S. Pat. No. 5,544,646 describes systems for theintrapulmonary delivery of aerosolized aqueous formulations. The systemdescribed allows unit dosed packages of aqueous formulated drug to bedelivered deep into the lung for systemic effect. U.S. Pat. No.5,558,085, Intrapulmonary Delivery of Peptide Drugs illustrates howproteins and peptides can be delivered as fine particle aerosols throughthe lung for systemic effect. U.S. Pat. No. 5,497,763 describes adisposable package for intrapulmonary delivery of aerosolizedformulations which allows sealed packets of preformulated drugs such asinsulin to be inserted by the patient into aerosolization apparatus forproducing fine particle aerosols for deep inhalation.

By quantitatively measuring the inspiratory flow rate and volume duringthe patients' inspiratory maneuver while breathing through theaerosolization system, an optimum point for the delivery of a bolus ofaerosolized medication can be determined. U.S. Pat. No. 5,509,404describes intrapulmonary drug delivery within therapeutically relevantinspiratory flow volume values and illustrates how specific inspiratoryflow rate and flow volume criteria can be used to enhance thereproducibility of drugs delivered via the lung for systemic effect.U.S. Pat. No. 5,522,385, Dynamic Particle Size Control for AerosolizedDrug Delivery demonstrates that the parameters of the emitted aerosolcan be varied to optimize the delivery of an inhaled aerosol forsystemic effect.

U.S. patent application Ser. No. 08/754,423, filed Nov. 11, 1996,illustrates that recombinant human insulin, when delivered as an aerosolfor deep inhalation into the lung for systemic effect, is sequestered inthe lung to a significant degree. This U.S. patent application describeshow insulin sequestered within the lung can be made to transit into thesystemic circulation if the patient engages in certain specificinspiratory maneuvers following delivery.

Although the reasons for sequestration of insulin in the lung followingaerosolized delivery are not known, we speculate that, as withsubcutaneous delivery, the dissociation of insulin from hexameric tomonomeric form is an important first step prior to the absorption ofinsulin into the blood stream. Recent controlled experiments conductedby the inventors quantified the degree to which insulin is sequesteredinto the lung following aerosolized delivery. In these controlledexperiments, the amount of insulin or monomeric insulin released intothe blood stream following aerosol delivery was quantified in cross overfashion with and then without a forced expiratory maneuver followingdelivery. Results shown here indicated that the blood concentrationversus time profile of monomeric insulin is not substantially affectedcompared to insulin by a patient's respiratory maneuver at delivery.

Although multiple studies have evaluated the feasibility of the deliveryof recombinant human insulin via the lung as a fine particle aerosol, nostudies have appeared demonstrating that recombinant human insulin issequestered in the lung following aerosolized delivery. Recentlyconducted clinical studies demonstrate that significant sequestration ofrecombinant human insulin is occurring in the lung following aerosoldrug delivery. Although this degree of sequestration can be reversed bycertain specific pulmonary maneuvers as shown in our copendingapplication, it will be desirable to substantially reduce or eliminatethis sequestration altogether.

Because Humalog™ rapidly disassociates into monomeric insulin, it isuniquely suited for delivery via the lung.

The invention includes containers, devices and methods which provide anon-invasive means of treating diabetes mellitus in a manner which makesit possible to accurately dose the administration of aerosolizedmonomeric insulin and thereby maintain tight control over serum glucoselevels of a patient suffering from the disease. The device of theinvention provides a number of features which make it possible toachieve the controlled and repeatable dosing procedure required fortreating diabetes.

Specifically, the device is not directly actuated by the patient in thesense that no button is pushed nor valve released by the patientapplying physical pressure. On the contrary, the device of the inventionprovides that aerosolized insulin formulation is released automaticallyupon receipt of a signal from a microprocessor programmed to send asignal when data is received from a monitoring device such as an airflowrate monitoring device.

A patient using the device withdraws air from a mouthpiece and theinspiratory rate of the patient is measured as is cumulative inspiratoryvolume. The monitoring device continually sends information to themicroprocessor, and when the microprocessor determines that the optimalpoint in the respiratory cycle is reached, the microprocessor actuatesthe opening of the valve allowing release of insulin. Accordingly, drugis always delivered at a pre-programmed place in the respiratory flowprofile of the particular patient which is selected specifically tomaximize reproducibility of drug delivery to the peripheral lungregions. It is pointed out that the device of the present invention canbe used to, and actually does, improve the efficiency of drug delivery.However, this is not a critical feature. Important features are theenhanced repeatability of blood concentration versus time profile andthe increased rate at which insulin is brought into the circulatorysystem. The invention makes it possible to deliver a tightly controlledamount of drug at a particular point in the inspiratory cycle so as toassure the delivery of a controlled and repeatable amount of drug to thelungs of each individual patient.

The automatic control of monomeric insulin release provides a repeatablemeans controlling the glucose level of a patient. Because aerosolizedmonomeric insulin formulation is released automatically and notmanually, it can predictably and repeatedly be released in the sameamount each time to provide a preprogrammed measured amount which isdesired.

When it is desirable to decrease particle size by heating, a heatingelement is used. The amount of heat added to the air is about 20 Joulesor more, preferably 20 Joules to about 100 Joules and more preferably 20Joules to about 50 Joules per 10 μl of formulation.

There is considerable variability with respect to the amount of insulinwhich is delivered to a patient when the insulin is being administeredby injection. Patients requiring the administration of injectableinsulin use commercial insulin which is prepared in concentrations of100 units per milliliter, although higher concentrations up to about1,000 units per milliliter can be obtained. It is preferable to use morehighly concentrated monomeric insulin in connection with the presentinvention. If insulin containing 500 units of insulin per milliliter isused and a patient is administering 25 units, then the patient will onlyneed to administer 0.05 milliliters of the concentrated insulin to thelungs of the patient to achieve the desired dose.

The symptoms of diabetes can be readily controlled with theadministration of insulin. However, it is extremely difficult, tonormalize the blood sugar throughout a 24-hour period utilizingtraditional insulin therapy given as one or two injections per day. Itis possible to more closely approach normalized blood sugar levels withthe present invention. Improvements are obtained by smaller, morefrequent dosing and by timing dosing relative to meals, exercise andsleep.

The precise amount of insulin administered to a patient variesconsiderably depending upon the degree of the disease and the size ofthe patient. A normal-weight adult may be started on about a 15-20 unitsa day (as explained above the units are equivalent subcutaneous units)in that the estimated daily insulin production rate in non-diabeticsubjects of normal size is approximately 25 units per day. It ispreferable to administer approximately the same quantity of insulin forseveral days before changing the dosing regime except with hypoglycemicpatients for which the dose should be immediately decreased unless aclearly evident nonrecurrent cause of hypoglycemia (such as not eating,i.e., missing a typical meal) is present. In general, the changes shouldnot be more than five to ten units per day. It is typical to administerabout two-thirds of the total insulin daily dosage before breakfast andadminister the remainder before supper. When the total dosage reaches 50or 60 units per day, a plurality of smaller doses are often requiredsince peak action of insulin appears to be dose related, i.e., a lowdose may exhibit maximal activity earlier and disappear sooner than alarge dose. All patients are generally instructed to reduce insulindosage by about 5 to 10 units per day when extra activity isanticipated. In a similar manner, a small amount of extra insulin may betaken before a meal that contains extra calories or food which is notgenerally eaten by the diabetic patient. The inhalation device of thepresent invention is particularly useful with respect to providing suchsmall amounts of additional insulin.

Several types of insulin formulations are commercially available. Whenlarger doses of insulin must be administered at a single point in time,it may be preferable to administer intermediate or long-acting insulinformulations. Such formulations release some insulin immediately andprovide a more sustained release of the remainder of the insulin overtime. Such formulations are described further below in the “InsulinContaining Formulations” section.

There is a differential between the amount of insulin and/or monomericinsulin actually released from the device and the amount actuallydelivered to the patient. The present device is two to ten times moreefficient than conventional inhalation devices (i.e., MDIs or metereddose inhalers) which have an efficiency as low as 10% meaning that aslittle as 10% of the aerosolized insulin may actually reach the lungs ofthe patient.

The efficiency of the delivery will vary somewhat from patient topatient and should be taken into account when programming the device forthe release of insulin.

One of the difficulties with aerosolized delivery of insulin is that thepatient and/or the caregiver cannot determine precisely how much insulinhas entered the circulatory system. Accordingly, if the patient has beendosed with what is believed to be an adequate amount of aerosolizedinsulin and the glucose level remains high one might assume that theaerosolized dose was not properly delivered. For example, the insulinmight have been improperly delivered against the patient's mouthsurfaces or throat where it will not be absorbed into the circulatorysystem. However, it may be that the insulin is properly delivered to thelung (e.g., provided on the outer peripheral areas of the lung) but hasnot yet migrated into the circulatory system.

Obese patients are generally somewhat less sensitive to insulin and mustbe provided with higher doses of insulin in order to achieve the sameeffect as normal weight patients. Dosing characteristics based oninsulin sensitivity are known to those skilled in the art and are takeninto consideration with respect to the administration of injectableinsulin. The present invention makes it possible to vary dosing overtime if insulin sensitivity changes and/or if user compliance and/orlung efficiency changes over time.

Based on the above, it will be understood that the dosing or amount ofmonomeric insulin actually released from the device can be changed basedon the most immediately prior monitoring event wherein the inspiratoryflow of a patient's inhalation is measured. The amount of insulinreleased can also be varied based on factors such as timing and timingis, in general, connected to meal times, sleep times and, to a certainextent, exercise times. Although all or any of these events can be usedto change the amount of insulin released from the device and thus theamount of insulin delivered to the patient, ultimately, the amountreleased and delivered to the patient is based on the patient's serumglucose levels. It is important to maintain the serum glucose levels ofthe patient within acceptable levels (greater than 60 mg/dl and lessthan 125 mg/100 ml, and most preferably to maintain those levels atabout 80 mg/100 ml.

Variations in doses are calculated by monitoring serum glucose levels inresponse to known amounts of insulin released from the device. If theresponse in decreasing serum glucose level is higher than with previousreadings, then the dosage is decreased. If the response in decreasingserum glucose level is lower than with previous readings, then thedosing amount is increased. The increases and decreases are gradual andare preferably based on averages (of 10 or more readings of glucoselevels after 10 or more dosing events) and not a single dosing event andmonitoring event with respect to serum glucose levels. The presentinvention can record dosing events and serum glucose levels over time,calculate averages and deduce preferred changes in administration ofinsulin.

As another feature of the invention, the device can be programmed so asto prevent the administration of more than a given amount of insulinwithin a given period of time. For example, if the patient normallyrequires 25 units per day of insulin, the microprocessor of theinhalation device can be programmed to prevent further release of thevalve after 35 units has been administered within a given day. Setting aslightly higher limit would allow for the patient to administeradditional insulin, if needed, due to larger than normal meals and/oraccount for misdelivery of insulin such as due to coughing or sneezingduring an attempted delivery.

The ability to prevent overdosing is a characteristic of the device dueto the ability of the device to monitor the amount of insulin releasedand calculate the approximate amount of insulin delivered to the patientbased on monitoring given events such as airflow rate and serum glucoselevels. The ability of the present device to prevent overdosing is notmerely a monitoring system which prevents further manual actuation of abutton. As indicated above, the device used in connection with thepresent invention is not manually actuated, but is fired in response toan electrical signal received from a microprocessor. Applicant's devicedoes not allow for the release of insulin merely by the manual actuationof a button to fire a burst of insulin into the air.

The microprocessor of applicant's invention can be designed so as toallow for an override feature which would allow for the administrationof additional insulin. The override feature could be actuated in anemergency situation. Alternatively, the override feature could beactuated when the device is electronically connected with a serumglucose level monitoring device which determines that serum glucoselevels increase to dangerously high levels.

The microprocessor of applicant's invention will preferably include atiming device. The timing device can be electrically connected withvisual display signals as well as audio alarm signals. Using the timingdevice, the microprocessor can be programmed so as to allow for a visualor audio signal to be sent when the patient would be normally expectedto administer insulin. In addition to indicating the time ofadministration (preferably by audio signal), the device can indicate theamount of insulin which should be administered by providing a visualdisplay. For example, the audio alarm could sound alerting the patientthat insulin should be administered. At the same time, the visualdisplay could indicate “five units” as the amount of insulin to beadministered. At this point, a monitoring event could take place. Afterthe predetermined dose of five units had been administered, the visualdisplay would indicate that the dosing event had ended. If the patientdid not complete the dosing event by administering the stated amount ofinsulin, the patient would be reminded of such by the initiation ofanother audio signal, followed by a visual display instructing thepatient to continue administration.

Additional information regarding dosing with insulin via injection canbe found within Harrison's—Principles of Internal Medicine (most recentedition) published by McGraw Hill Book Company, New York, incorporatedherein by reference to disclose conventional information regardingdosing insulin via injection.

Treatment Via Monomeric Insulin

The methodologies of the present invention are preferably carried outusing recombinantly produced monomeric insulin in a liquid formulation.A preferred insulin is insulin lispro, sold by Lilly under the nameHumalog™. This analog is absorbed faster after subcutaneous injection.Another type of insulin analog is referred to as superactive insulin. Ingeneral, superactive insulin has increased activity over natural humaninsulin. Accordingly, such insulin can be administered in substantiallysmaller amounts while obtaining substantially the same effect withrespect to reducing serum glucose levels. Another general type of analogis referred to as hepatospecific insulin. Hepatospecific insulin analogsare more active in the liver than in adipose tissue and offer severaladvantages over currently available insulin therapy. Hepatospecificanalogs provide preferential hepatic uptake during peripheralsubcutaneous administration, thereby mimicking, more closely, themetabolic balance between the liver and the peripheral tissues.Obtaining the correct metabolic balance is an important part of propertreatment of diabetics and administration via the intrapulmonary routeshould provide advantages over intermuscular injection with respect toobtaining such a balance. It may be desirable to include mixtures ofconventional insulin with insulin lispro or with insulin which ishepatospecific and/or with superactive insulin analogs. Hepatospecificanalogs are disclosed and described within published PCT applicationWO90/12814, published Nov. 1, 1990, which application is incorporatedherein by reference for its disclosure of such hepatospecific insulinanalogs and in order to disclose other information cited within theother publications referred to within WO90/12814. To carry out theinvention these insulins must be in a monomeric form or take a monomericform quickly in a human.

U.S. patent application Ser. No. 074,558 discloses a superactive humaninsulin analog, [10-Aspartic Acid-B] human insulin, which has increasedactivity over natural human insulin. Specifically, [10-Aspartic Acid-B]human insulin was determined to be 4 to 5 times more potent than naturalinsulins. U.S. patent application Ser. No. 273,957 and InternationalApplication Ser. No. PCT/US88/02289 disclose other superactive insulinanalogs, des-pentapeptide (B26-B30)-[Asp^(B10), Tyr^(B25)-α-carboxamide]human insulin, (B26-B30)-[Glu^(B10), Tyr^(B25)-α-carboxamide] humaninsulin, and further insulin analogs of the formulades(B26-B30)-[X^(B10), Tyr^(B25)-α-carboxamide] human insulin, in whichX is a residue substituted at position 10 of the B chain. These insulinanalogs have potencies anywhere from 11 to 20 times that of naturalhuman insulin. All of the above-described insulin analogs involve aminoacid substitutions along the A or B chains of natural human insulin,which increase the potency of the compound or change other properties ofthe compound.

Other than insulin lispro the insulin analogs are not presently used forthe treatment of patients on a commercial scale. However, insulin lisproand other insulin analogs being developed could be used with the presentinvention in that the present invention can be used to provide variabledosing in response to currently measured serum glucose levels. Further,since many insulin analogs are more potent than conventional insulin,their delivery via the intrapulmonary route is particularly convenient.

Information regarding dosing insulin can be found withinHarrison's—Principles of Internal Medicine (most recent edition) and theDrug Evaluation Manual, 1993 (AMA—Division of Drugs and Toxicology),both of which are published by McGraw Hill Book Company, New York,incorporated herein by reference to disclose conventional informationregarding dosing of insulin.

Monitoring Diabetic Control

All methods of treating diabetes involve measuring glucose levels insome manner. Such measurements are necessary in order to titrate properdosing and avoid the over-administration of insulin which can result infatal hypoglycemia. Measurements of urine glucose alone are insufficientto assess diabetic control and bring mean plasma glucose values into anear normal range since the urine will be free of glucose when theplasma concentration is relatively normal. For this reason, “homeglucose monitoring” is used in those patients treated by continuoussubcutaneous insulin infusion (CSH) or multiple subcutaneous injection(MSI) techniques. Such monitoring requires capillary blood which can beobtained in a substantially painless manner using a smallspring-triggered device referred to as Autolet™ produced by UlstrScientific Incorporated which device is equipped with small disposablelancelets. The amount of glucose is analyzed using chemicallyimpregnated strips which are read in a commercially availablereflectance meter. One commercially available strip is referred to asChemstrip bG (produced by Bio-Dynamics). The Chemstrip Bg can providesatisfactory values by visual inspection utilizing a dual-color scale,thus eliminating the need for a reflectance meter. Frequent measurementof the plasma glucose (a fairly standard program utilizes seven or eightassays over a 24-hour period) allows a reasonable assessment of meanplasma glucose levels during the day and guides adjustment of insulindosage.

The methodology of the present invention is preferably utilized incombination with a closely controlled means of monitoring serum glucoselevels. More specifically, the invention is used to administer doses ofmonomeric insulin via the intrapulmonary route. The doses may beadministered more frequently but in somewhat smaller amounts than aregenerally administered by injection. The amount of insulin and monomericinsulin administered can be readily adjusted in that smaller amounts aregenerally administered using the intrapulmonary delivery methodology ofthe present invention.

During the day, as insulin is administered, serum glucose levels arefrequently monitored. The amount of insulin administered can be dosedbased on the monitored serum glucose levels, i.e., as glucose levelsincrease, the amount of insulin can be increased, and as glucose levelsare seen to decrease, the dosing of insulin can be decreased.

Based on the information disclosed herein in combination with what isknown about insulin dosing and serum glucose levels, computer readableprograms can be readily developed which can be used in connection withthe insulin delivery device of the present invention. More specifically,a microprocessor of the type disclosed in U.S. Pat. No. 5,542,410 can beprogrammed so as to deliver precise doses of insulin which correspond tothe particular needs of the patient based on serum glucose monitoringinformation which is supplied to the microprocessor. Further, the dosinginformation contained within the microprocessor can be fed to a separatecomputer and/or serum glucose monitoring device (preferably portable) inorder to calculate the best treatment and dosing schedule for theparticular patient.

Insulin Containing Formulations

A variety of different monomeric insulin containing formulations can beused in connection with the present invention. The active ingredientwithin such formulations is monomeric insulin which can be combined withregular insulin. Further, the monomeric insulin may be combined with aninsulin analog which is an analog of human insulin which has beenrecombinantly produced. Although the monomeric insulin is generallypresent by itself as the sole active ingredient, it may be present withan additional active ingredient such as a sulfonylurea. However, suchsulfonylureas are generally administered separately in order to moreclosely control dosing and serum glucose levels.

The present invention provides a great deal of flexibility with respectto the types of monomeric insulin formulations to be administered. Forexample, a container can include monomeric insulin by itself or incombination with an analog of any type or combinations of differentinsulin analogs. Further, a package can be created wherein individualcontainers include different formulations wherein the formulations aredesigned to achieve a particular effect e.g., fast acting insulin orquick absorbing insulin. The patient along with the care giver andcareful monitoring can determine the preferred insulin dosing protocolto be followed for the particular patient.

The monomeric insulin may be provided as a dry powder by itself, and inaccordance with another formulation, the insulin or active ingredient isprovided in a solution formulation. The dry powder could be directlyinhaled by allowing inhalation only at the same measured inspiratoryflow rate and inspiratory volume for each delivery. However, the powderis preferably dissolved in an aqueous solvent to create a solution whichis moved through a porous membrane to create an aerosol for inhalation.

Any formulation which makes it possible to produce aerosolized forms ofmonomeric insulin which can be inhaled and delivered to a patient viathe intrapulmonary route can be used in connection with the presentinvention. Specific information regarding formulations (which can beused in connection with aerosolized delivery devices) is describedwithin Remington's Pharmaceutical Sciences, A. R. Gennaro editor (latestedition) Mack Publishing Company. Regarding insulin formulations, it isalso useful to note Sciarra et al. [Journal of Pharmaceutical Sciences,Vol. 65, No. 4, 1976].

The monomeric insulin is preferably included in a solution such as thetype of solution which is made commercially available for injectionand/or other solutions which are more acceptable for intrapulmonarydelivery. When preparing preferred formulations of the invention whichprovide for the monomeric insulin, excipient and solvent, anypharmaceutically acceptable excipient may be used provided it is nottoxic in the respiratory tract. The monomeric insulin formulationpreferably has a pH of about 7.4±1.0.

Formulations include monomeric insulin dry powder by itself and/or withan excipient. When such a formulation is used, it may be used incombination with a gas propellant which gas propellant is released overa predetermined amount of dried powder which is forced into the air andinhaled by the patient. It is also possible to design the device so thata predetermined amount of dry powder is placed behind a gate. The gateis opened in the same manner as the valve is released so that the sameinspiratory flow rate and inspiratory volume is repeatedly obtained.Thereafter, the dry powder is inhaled by the patient and the insulin isdelivered.

Rapidly acting preparations are always indicated in diabetic emergenciesand in CSII and MSI programs. Intermediate preparations are used inconventional and MSI regimens. It is not possible to delineate preciselythe biologic responses to the various preparations because peak effectsand duration vary from patient to patient and depend not only on routeof administration but on dose. The various insulins are available asrapid (regular, semilente), intermediate (NPH, lente, globin), andlong-acing (PZI, ultralente) preparations, although not allmanufacturers offer all varieties. Lente and NPH insulin are used inmost conventional therapy and are roughly equivalent in biologiceffects. These can be used with monomeric insulin.

The methodology of the invention may be carried out using a portable,hand-held, battery-powered device which uses a microprocessor componentas disclosed in U.S. Pat. Nos. 5,404,871, issued Apr. 11, 1995 and5,450,336, issued Sep. 12, 1995 both of which are incorporated herein byreference. In accordance with another system the methodology of theinvention could be carried out using the device, dosage units and systemdisclosed in U.S. Pat. No. 94/05825 with modifications as describedherein. Monomeric insulin is included in an aqueous formulation which isaerosolized by moving the formulation through a flexible porousmembrane. Alternatively, the methodology of the invention could becarried out using a mechanical (non-electronic) device. Those skilled inthe art recognized that various components can be mechanical set toactuate at a given inspiratory flow rate (e.g. a spring biased valve)and at a given volume (e.g. a spinable flywheel which rotates a givenamount per a given volume). The components of such devices could be setto allow drug release inside defined parameters.

The monomeric insulin which is released to the patient may be in avariety of different forms. For example, the insulin may be an aqueoussolution of drug, i.e., drug dissolved in water and formed into smallparticles to create an aerosol which is delivered to the patient.Alternatively, the drug may be in a solution or a suspension wherein alow-boiling point propellant is used as a carrier fluid. In yet, anotherembodiment the insulin may be in the form of a dry powder which isintermixed with an airflow in order to provide for delivery of drug tothe patient. Regardless of the type of drug or the form of the drugformulation, it is preferable to create drug particles having a size inthe range of about 0.5 to 12 microns, more preferably 1-4 microns. Bycreating drug particles which have a relatively narrow range of size, itis possible to further increase the efficiency of the drug deliverysystem and improve the repeatability of the dosing. Thus, it ispreferable that the particles not only have a size in the range of 0.5to 12 microns but that the mean particle size be within a narrow rangeso that 80% or more of the particles being delivered to a patient have aparticle diameter which is within ±20% of the average particle size,preferably ±10% and more preferably ±5% of the average particle size.

An aerosol may be created by forcing drug through pores of a membranewhich pores have a size in the range of about 0.25 to 6 micronspreferably 0.5 to 3.0 microns. When the pores have this size theparticles in the aerosol will have a diameter about twice the diameterof the pore opening from which the formulation exits. However, theparticle size can be substantially reduced by adding heat to the airaround the particles and cause evaporation of carrier. Drug particlesmay be released with an air flow intended to keep the particles withinthis size range. The creation of small particles may be facilitated bythe use of the vibration device which provides a vibration frequency inthe range of about 800 to about 4000 kilohertz. Those skilled in the artwill recognize that some adjustments can be made in the parameters suchas the size of the pores from which drug is released, vibrationfrequency and amplitude, pressure, and other parameters based on theconcentration, density, viscosity and surface tension of the formulationkeeping in mind that the object is to provide aerosolized particleshaving a diameter in the range of about 0.25 to 12 microns, preferably1.0-3.0 microns.

The drug formulation may be a low viscosity liquid formulation. Theviscosity of the drug by itself or in combination with a carrier is notof particular importance except to note that the formulation preferablyhas characteristics such that it can be forced out of openings of theflexible or convex membrane to form an aerosol, e.g., using 20 to 400psi to form an aerosol preferably having a particle size in the range ofabout 0.5 to 6.0 microns.

Drug may be stored in and/or released from a container of any desiredsize. In most cases the size of the container is not directly related tothe amount of drug being delivered in that most formulations includerelatively large amounts of excipient material e.g. water or a salinesolution. Accordingly, a given size container could include a wide rangeof different doses by varying drug concentration.

Drug containers may include indices which may be electronic and may beconnected to a power source such as a battery. When the indices are inthe form of visually perceivable numbers, letters or any type of symbolcapable of conveying information to the patient. Alternatively, theindices may be connected to a power source such as a battery when theindices are in the form of magnetically, optically or electronicallyrecorded information which can be read by a drug dispensing device whichin turn provides visual or audio information to the user. The indicescan be designed for any desired purpose but in general provide specificinformation relating to the day and/or time when the drug within acontainer should be administered to the patient. Such indices mayrecord, store and transfer information to a drug dispensing deviceregarding the number of doses remaining in the container. The containersmay include labeling which can be in any format and could include daysof the month or other symbols or numbers in any variation or language.

In addition to disclosing specific information regarding the day andtime for drug delivery the indices could provide more detailedinformation such as the amount of insulin dispensed from each containerwhich might be particularly useful if the containers included differentamounts of insulin. The device may dispense all or any desiredpercentage amount (1-100%) of the insulin in the container. The devicekeeps a record of the amount dispensed and the container can be reusedwithin a given period of time (e.g., 2 hours or less) to dispense theremainder of the insulin in a given container. However, it is preferableto discard a container after use even if all the formulation is notexpelled. This ensures freshness and reduces contamination. Further,magnetic, optical and/or electronic indices could have new informationrecorded onto them which information could be placed there by the drugdispensing device. For example, a magnetic recording means could receiveinformation from the drug dispensing device indicating the precise time(and amount) which the insulin was actually administered to the patient.In addition to recording the time of delivery the device could monitorthe expected efficacy of the delivery based on factors such as theinspiratory flow rate which occurred following the initial release ofinsulin. The information recorded could then be read by a separatedevice, interpreted by the care-giver and used to determine theusefulness of the present treatment methodology. For example, if theglucose levels of the patient did not appear to be responding well butthe recorded information indicating that the patient had taken the drugat the wrong time or that the patient had misdelivered drug by changinginspiratory flow rate after initial release it might be determined thatfurther education in patient use of the device was needed but that thepresent dosing methodology might well be useful. However, if therecordings indicated that the patient had delivered the aerosolizedinsulin using the proper techniques and still not obtained the correctresults (e.g. acceptable glucose levels) another dosing methodologymight be recommended. The method of treating diabetes mellitus may becarried out using a hand-held, portable device comprised of (a) a devicefor holding a disposable package comprised of at least one butpreferably a number of drug containers, (b) a propellant or a mechanicalmechanism for moving the contents of a container through a porousmembrane (c) a monitor for analyzing the inspiratory flow rate andvolume of a patient, and (d) a switch for automatically releasing orfiring the mechanical means after the inspiratory flow and/or volumereaches a threshold level. The device may also include a transportmechanism to move the package from one container to the next with eachcontainer and its porous membrane being disposed of after use.Containers are preferably used only 1,2,3 or 4 times, at most. If usedmore than once, the remainder in the container is used in 2 hours orless and/or disposed of The entire device is self-contained,light-weight (less than 1 kg preferably less than 0.5 kg loaded) andportable.

The device may include a mouth piece at the end of the flow path, andthe patient inhales from the mouth piece which causes an inspiratoryflow to be measured within the flow path which path may be in anon-linear flow-pressure relationship. This inspiratory flow causes anairflow air flow transducer to generate a signal. This signal isconveyed to a microprocessor which is able to convert, continuously, thesignal from the transducer in the inspiratory flow path to a flow ratein liters per minute. The microprocessor can further integrate thiscontinuous air flow rate signal into a representation of cumulativeinspiratory volume. At an appropriate point in the inspiratory cycle,the microprocessor can send a signal to an actuation means (and/or avibration device below the resonance cavity). When the actuation meansis signaled, it causes the mechanical means (by pressure and/orvibration) to move drug from a container on the package into theinspiratory flow path of the device and ultimately into the patient'slungs. After being released, the drug and carrier will pass through aporous membrane, which can be vibrated to aerosolize the formulation andthereafter enter the lungs of the patient.

It is important to note that the firing threshold of the device is notbased on a single criterion such as the rate of air flow through thedevice or a specific time after the patient begins inhalation. Thefiring threshold is preferably based on repeating the firing at the sameflow rate and volume. This means that the microprocessor controlling thedevice takes into consideration the instantaneous air flow rate as wellas the cumulative inspiratory flow volume. Both are simultaneouslyconsidered together in order to determine the optimal point in thepatient's inspiratory cycle most preferable in terms of (1) reproduciblydelivering the same amount of drug to the patient with each release ofdrug by releasing drug at the same point each time and (2) maximizingthe amount of drug delivered as a percentage of the total amount of drugreleased by releasing with the parameters described herein.

The device preferably includes a means for recording a characterizationof the inspiratory flow profile for the patient which is possible byincluding a microprocessor in combination with a read/write memory meansand a flow measurement transducer. By using such devices, it is possibleto change the firing threshold at any time in response to an analysis ofthe patient's inspiratory flow profile, and it is also possible torecord drug dosing events over time. In a particularly preferredembodiment the characterization of the inspiratory flow can be recordedonto a recording means associated with disposable package.

The details of a drug delivery device which includes a microprocessorand pressure transducer of the type which may be used in connection withthe present invention are described and disclosed within U.S. Pat. Nos.5,404,871, issued Apr. 11, 1995 and 5,450,336, issued Sep. 12, 1995incorporated in their entirety herein by reference, and specificallyincorporated in order to describe and disclose the microprocessor andprogram technology used therewith. The pre-programmed information iscontained within a nonvolatile memory which can be modified via anexternal device. In another embodiment, this pre-programmed informationis contained within a “read only” memory which can be unplugged from thedevice and replaced with another memory unit containing differentprogramming information. In yet another embodiment, a microprocessor,containing read only memory which in turn contains the pre-programmedinformation, is plugged into the device. For each of these embodiments,changing the programming of the memory device readable by amicroprocessor will radically change the behavior of the device bycausing the microprocessor to be programmed in a different manner. Thisis done to accommodate different insulin formulation and for differenttypes of treatment, e.g., patients with different types of diabetes.

After dosing a patient with insulin it is desirable to measure glucose(invasively or non-invasively) and make adjustments as needed to obtainthe desired glucose level. In accordance with all methods the patientdoes not push a button to release drug. The drug is releasedautomatically by signals from the microprocessor using measurementsobtained.

The doses administered are based on an assumption that whenintrapulmonary delivery methodology is used the efficiency of thedelivery is at a known percent amount, e.g., approximately 20% to 50% ormore and adjustments in the amount released in order to take intoaccount the efficiency of the device. The differential between theamount of insulin actually released from any device and the amountactually delivered to the patient varies due to a number of factors. Ingeneral, devices used with the present invention can have an efficiencyas low as 10% and as high as 50% or more meaning that as little as 10%of the released insulin may actually reach the circulatory system of thepatient and as much as 50% or more might be delivered. The efficiency ofthe delivery will vary somewhat from patient to patient and must betaken into account when programming the device for the release ofinsulin. In general, a conventional metered (propellant-driven) doseinhaling device is about 10% efficient.

One of the features and advantages of the present invention is that themicroprocessor can be programmed to take a variety of different criteriainto consideration with respect to dosing times. Specifically, themicroprocessor can be programmed so as to include a minimum timeinterval between doses i.e. after a given delivery another dose cannotbe delivered until a given period of time has passed. Secondly, thetiming of the device can be programmed so that it is not possible toexceed the administration of a set maximum amount of insulin within agiven time. For example, the device could be programmed to preventdispersing more than 5 units of insulin within one hour. Moreimportantly, the device can be programmed to take both criteria intoconsideration. Thus, the device can be programmed to include a minimumtime interval between doses and a maximum amount of insulin to bereleased within a given time period. For example, the microprocessorcould be programmed to allow the release of a maximum of 5 units ofinsulin during an hour which could only be released in amounts of 1 unitwith each release being separated by a minimum of five minutes.

Additional information regarding dosing with insulin via injection canbe found within Harrison's—Principles of Internal Medicine (most recentedition) published by McGraw Hill Book Company, New York, incorporatedherein by reference to disclose conventional information regardingdosing insulin via injection.

Another feature of the device is that it may be programmed not torelease drug if it does not receive a signal transmitted to it by atransmitter worn by the intended user. Such a system improves thesecurity of the device and prevents misuse by unauthorized users such aschildren.

The microprocessor of the invention can be connected to external devicespermitting external information to be transferred into themicroprocessor of the invention and stored within the non-volatileread/write memory available to the microprocessor. The microprocessor ofthe invention can then change its drug delivery behavior based on hisinformation transferred from external devices such as a glucosemonitoring device. All of the features of the invention are provided ina portable, programmable, battery-powered, hand-held device for patientuse which has a size which compares favorably with existing metered doseinhaler devices.

Different mechanisms will be necessary in order to deliver differentformulations, such as a dry powder without any propellant. A devicecould be readily designed so as to provide for the mechanical movementof a predetermined amount of dry powder to a given area. The dry powderwould be concealed by a gate, which gate would be opened in the samemanner described above, i.e., it would be opened when a predeterminedflow rate level and cumulative volume have been achieved based on anearlier monitoring event. Patient inhalation or other source of energysuch as from compressed gas or a mechanical device would then cause thedry powder to form a dry dust cloud and be inhaled.

In addition to monitoring glucose levels in order to determine properinsulin dosing, the microprocessor of the present invention isprogrammed so as to allow for monitoring and recording data from theinspiratory flow monitor without delivering drug. This is done in orderto characterize the patient's inspiratory flow profile in a given numberof monitoring events, which monitoring events preferably occur prior todosing events. After carrying out a monitoring event, the preferredpoint within the inspiratory cycle for drug delivery can be calculated.This calculated point is a function of measured inspiratory flow rate aswell as calculated cumulative inspiratory flow volume. This informationis stored and used to allow activation of the valve when the inhalationcycle is repeated during the dosing event. Those skilled in the art willalso readily recognize that different mechanisms will be necessary inorder to deliver different formulations, such as a dry powder withoutany propellant. A device could be readily designed so as to provide forthe mechanical movement of a predetermined amount of dry powder to agiven area. The dry powder would be concealed by a gate, which gatewould be opened in the same manner described above, i.e., it would beopened when a predetermined flow rate level and cumulative volume havebeen achieved based on an earlier monitoring event. Patient inhalationwould then cause the dry powder to form a dry dust cloud and be inhaled.Dry powder can also be aerosolized by compressed gas, and a solution canbe aerosolized by a compressed gas released in a similar manner and theninhaled.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use various constructs and perform the various methods of thepresent invention and are not intended to limit the scope of what theinventors regard as their invention. Efforts have been made to ensureaccuracy with respect to numbers used (e.g. amounts, concentrations,particular components, etc.) but some deviations should be accountedfor.

Example 1 Administration of Regular Recombinant Human Insulin

A study was performed to determine the influence of different inhalationmaneuvers: deep (V_(H)) and shallower (V_(L)) inhalation. Deepinhalations required the patients to inhale as much as possible (e.g.,4-5 liters) and shallow inhalation were about half that (e.g. 2-2.5liters) following the administration of aerosolized drug). The study wasperformed using five healthy, fasting male subjects. To each of thesubjects, 250 U/ml of a 7.4 pH human zinc insulin formulation wasadministered using three methods: subcutaneous administration, deepinhalation administration, or shallow inhalation administration.

The study was performed using five healthy, fasting male subjects. 250U/ml of a 3.5 pH human insulin formulation was administered to each ofthe subjects using three methods: subcutaneous administration, V_(H)inhalation administration and V_(L) administration. Subcutaneousadministration of the insulin consisted of an injection of apredetermined dosage into the subcutaneous region of the abdominal area.Aerosol administration to each subject was performed using a unit-dosed,breath-actuated microprocessor controlled device (AERx™), such as thedevice disclosed in the present application (see U.S. Pat. No. 5,660,166issued Aug. 26, 1997).

Serial serum blood samples were taken from each subject for the analysisof plasma glucose. The inhalation method resulted in a more rapidinitial change, and experienced a plateau at approximately a −20% changein plasma glucose. The subcutaneous administration resulted in a slowerresponse initially, achieving a later plateau at approximately a −25%change in glucose response.

The pharmacokinetic parameters—C_(max), the maximum serum insulinconcentration achieved in each subject, and T_(max), the amount of timeneeded for subjects to reach C_(max) after administration weredetermined for each subject, and (summarized in Table 1). The deepinhalation method showed a 10-fold decrease in T_(max).

TABLE 1 Inhaled human insulin: effect of mode of administrationParameter (mean ± SD) AERx-V_(H) AERx-V_(L) T_(max) (min)   5 ± 6   51 ±18 C_(max) (μU/ml) 26.7 ± 9.1 20.9 ± 8.1

Serum insulin profiles of each of the three modes of administration showsimilar peaks before tapering off over a three hour period (FIG. 1). TheAERx device V_(H) administration peaks much sooner and at a higherconcentration than the other methods, peaking at approximately 26 μU/mlat about 20 minutes. The AERx device V_(L) administration results in aslightly later and lower peak at one hour. Subcutaneous injection alsoresults in a later peak.

The study conducted with the regular zinc insulin pH 7.4 showed theimportance of the breathing technique in the administration of thisparticular insulin formulation, as controlled, deep breathing promotedrapid insulin absorption.

The results of experiment 1 demonstrate one aspect of the presentinvention. Specifically, the results show that it is important tocontrol the inhaled volume when inhaling an aerosolized dose of regularinsulin. Thus, one aspect of the invention involves measuring apatient's inhaled volume at delivery in order (1) repeatedly deliverwith the same inhaled volume each time to ensure repeatability ofdosing; and (2) prompt the patient to inhale a high volume, e.g. 80%plus or minus 15% of lung capacity with each inhalation. The promptingto inhale a high volume can be carried out by sending a signal to thepatient from a device which measures the inspiratory volume during drugdelivery.

Example 2 Determination of Efficacy of Administration of AerosolizedHuman Insulin Lispro

Modes of Administration

Pharmacokinetic parameters associated with the two modes of insulinadministration, inhalation of aerosolized insulin lispro andsubcutaneous injection of insulin lispro, were determined to compare theefficacy (bioeffectiveness in reducing glucose levels) and speed ofeach. The study was performed using nine healthy, fasted male subjects.

Aerosol administration to each subject was performed using the AERx™device. Administration was done using both deep (V_(H)) and shallower(V_(L)) inhaled administration—in 5 out of 9 subjects. Subcutaneousadministration of the insulin lispro consisted of an injection of apredetermined dosage into the subcutaneous region of the abdominal area.Serial serum blood samples were taken from each subject for the analysisof plasma glucose and serum insulin.

The pharmacokinetic parameters C_(max) and T_(max) were determined foreach subject. (Table 2). T_(max) was earlier following inhalationadministration of insulin lispro, indicating a more rapid absorptionfrom the lung as compared to SC administration. Thus, the mode ofinhalation (V_(H) or V_(L)) did not appear to significantly effectpharmacokinetics of the delivery of inhaled insulin lispro as comparedto the affect of V_(L) and V_(H) on the delivering of regular insulin.

TABLE 2 Pharmacokinetic parameters after insulin lispro administration(systematic study, n = 5) Parameter AERx-V_(H) AERx-V_(L) (mean ± SD)(0.3 U/kg) (0.3 U/kg) T_(max) (min)  9 ± 2 18 ± 15 C_(max) (μU/ml) 46 ±12 49 ± 12

In contrast to data obtained for aerosolized delivery of regular humaninsulin, the mode of inhalation did not lead to changes in the seruminsulin levels following administration of insulin lispro—compare FIGS.1 and 2.

The results in Tables 1 and 2 can be compared to show that the totalinhaled volume at delivery greatly effects results when administeringregular human recombinant insulin (Table 1) but has much less of aneffect when administering insulin lispro. As shown in FIG. 2, the bloodconcentration versus time insulin lispro is virtually the same for boththe V_(H) and V_(L) maneuvers. This surprising result indicates thatrepeatability of dosing can be more readily obtained with theadministration of insulin lispro by inhalation as compared withconventional insulin by inhalation. The results shown here indicate thatwhen delivering insulin (not monomeric insulin) by inhalation the totalinhaled volume should be about the same at each delivery to obtainrepeatable delivery. Thus, referring to FIG. 3, insulin is released atthe same point 1 for each release and then the patient continues toinhale to the same point 3 or 4. Preferably, the patient continues toinhale to point 4 or higher each time to obtain repeatable delivery.

The foregoing invention has been described in some detail by way ofillustration and example for purposes of clarity of understanding. Theinstant invention is shown herein in what is considered to be the mostpractical and preferred embodiments. It is recognized, however, thatdepartures may be made therefrom which are within the scope of theinvention and that obvious modifications will occur to one skilled inthe art upon reading this disclosure. Accordingly, the invention islimited only by the following claims.

1. A method of treating diabetes mellitus in a diabetic patient in needthereof, by reproducibly dosing insulin for systemic effect to thepatient's circulatory system via the patient's lungs in order to obtainan acceptable blood glucose level in the diabetic patient therebyreducing or eliminating the need for injection of insulin in thediabetic patient, said method comprising: (a) supplying a predeterminedamount of powdered insulin to a hand held device, said predeterminedamount being in excess of that amount required, in the bloodstream ofsaid patient, to produce or maintain an acceptable serum glucose levelin said patient; (b) exhaling; (c) contacting said insulin with acompressed gas to form a cloud in said hand held device, said cloudcomprising a repeatable amount of insulin, said repeatable amount beingin excess of that amount required, in the bloodstream of said patient,to produce or maintain an acceptable serum glucose level in saidpatient, said cloud comprising insulin particles in the range between0.5 and 6 microns; and (d) inhaling said cloud at an inspiratory flowrate in the range of 0.1 to 2.0 liters per second and wherein theinhaling of said cloud occurs with a high volume that comprises 65% to100% of the patient's total lung volume; (e) producing an acceptableblood glucose level in the diabetic patient, wherein the acceptableblood glucose level is produced by systemically absorbing a controlleddose of insulin that comprises a percentage of the supplied amount ofpowdered insulin.
 2. The method of claim 1, wherein the inhalation inthe inhaling step is performed by making a maximal effort to inhale. 3.The method of claim 1, wherein the aerosol is comprised of human insulinparticles between about 1 and 4 microns and occurs with a pressure lessthan 400 psi.
 4. The method of claim 1 wherein the patient is a patientwith type II diabetes, and wherein the insulin cloud comprises humaninsulin particles having a size in the range of about 1-3 microns. 5.The method of claim 1, further comprising repeating steps a-e, whereinin each repetition of steps a-e, the patient inhales substantially thesame volume of air with the cloud of insulin.
 6. The method of claim 5,wherein the inhaling occurs at substantially the same flow rate.
 7. Themethod of claim 1, further comprising the step of performing a breathhold for a predetermined period of time immediately after the inhalingstep.
 8. The method of claim 1, wherein the insulin is human insulin. 9.A method of treating diabetes mellitus in a patient in need thereof, byadministering insulin replacement therapy for systemic effect deliveredby inhalation in order to eliminate or reduce the need for injections ofinsulin, said method comprising: supplying a predetermined amount ofpowdered insulin to a mechanical hand held device, said predeterminedamount being in excess of that amount required, in the bloodstream ofsaid patient, to produce or maintain an acceptable serum glucose levelin said patient; contacting said insulin with a compressed gas to form acloud in a given area of said hand held device, said cloud comprising arepeatable amount of insulin, said repeatable amount being in excess ofthat amount required, in the bloodstream of said patient, to produce ormaintain an acceptable serum glucose level in said patient, said cloudcomprising insulin particles in the range between 0.5 and 6 microns;exhaling a determined volume of air; inhaling said cloud at aninspiratory flow rate in the range of 0.1 to 2.0 liters per second andwherein the inhaling of said cloud occurs with a high volume thatcomprises 65% to 100% of the patient's total lung volume; producing anacceptable blood glucose level in the patient, wherein the acceptableglucose level is produced by systemically absorbing a controlled dose ofinsulin that comprises a percentage of the supplied amount of powderedinsulin; repeating the above steps when the patient's blood glucoselevels rise or are expected to rise above a predetermined range andwherein for each repetition of the inhalation, the patient inhalessubstantially the same total volume.
 10. The method of claim 9, whereinthe insulin cloud is administered to the patient at substantially thesame point of inspiration each time the inhaling step is repeated andwherein the patient continues to inhale after the cloud is inhaled andwherein the inhalation continues to a determined point in theinspiratory cycle that is substantially the same each time the inhalingstep is repeated.
 11. The method of claim 9, further comprising the stepof performing a breath hold for a predetermined period of timeimmediately after the inhaling step.
 12. The method of claim 9, whereinthe insulin is human insulin.
 13. A method of administering a controlledand repeatable dose of insulin to a diabetic patient that is sufficientto control the patient's blood glucose level, the method comprising thesteps of: supplying a predetermined amount of dry insulin powder to ahand held mechanical inhalation device; contacting the powder with avolume of air in a given area of the hand held device to form a standingcloud comprised of human insulin particles and air in the given area ofthe hand held device; exhaling a volume of air; inhaling the insulin andair cloud, followed by continual inhalation with additional air until adetermined point of inspiration is reached, wherein the point is a pointV_((h)) corresponding to a high volume and wherein it is determined bycoaching (by teaching) the patient to inhale to high volume, whichcorresponds to 65% to 100% of total lung volume; wherein when the abovesteps are repeated in order to administer subsequent doses of insulinthe patient, as a result of the coaching, inhales each subsequent dosewith about the same high volume by inhaling to about the same determinedpoint V_((h)).
 14. The method of claim 13, wherein the determined pointis determined by making a maximal effort to inhale.
 15. The method ofclaim 13, wherein the exhaled volume is a determined volume and when thesteps are repeated in order to administer subsequent doses eachdetermined volume of exhaled air is substantially the same.
 16. Themethod of claim 15, wherein the flow rate during inhalation ismaintained at a rate of under 2 liters per second, and wherein theinhaling step is immediately followed by a breath holding step thatcomprises performing a breath hold for a predetermined period of time.17. The method of claim 16, wherein the flow rate during inhalation issubstantially the same for each repetition of the inhalation.
 18. Themethod of claim 15, wherein the insulin cloud is inhaled before thepatient inhales 0.8 liters of air.
 19. The method of 18, wherein thetotal inhaled volume during the inhalation step is a determined volumethat is determined by coaching the patient to perform a specificbreathing maneuver.
 20. The method of claim 19, wherein the specificmaneuver comprises inhaling with a maximal effort.
 21. The method ofclaim 19, wherein the inhaling occurs at a flow rate under about 1liters per second and wherein the flow rate for each repetition of theinhaling step is substantially the same.
 22. The method of claim 21,wherein the inhaling of the insulin cloud occurs at substantially thesame accumulated inspiratory volume for each repetition of the inhalingstep, and wherein the method further comprises a breath holding stepimmediately after the inhaling step and wherein for each repetition thebreath holding step comprises holding of breath for substantially thesame predetermined period of time.
 23. The method of claim 22, whereinthe determined point in each repetition of the inhaling step results ina determined volume being inhaled wherein the determined volume issubstantially the same for each inhaling step and wherein the determinedvolume is determined by coaching a patient to perform a specifiedbreathing maneuver, wherein the insulin cloud comprises a mixture ofinsulin and air.
 24. The method of claim 13, further comprising the stepof performing a breath hold for a predetermined period of timeimmediately after the inhaling step.